Antibody to cardiolipin (aCL) is an important predictor of fetal loss and other clinical events in patients with systemic lupus erythematosus. How the antibody is related to these events is unknown. The planned research will attempt to (1) clarify the immunochemistry of the interaction of aCL with phospholipids, (2) establish a patholphysiology that explains the clinical events, and (3) identify origins of the aCL. Affinity-purified aCL will be used to identify the primary phospholipid to which aCL is directed, to verify or refute the hypothesis that aCL binds to cardiolipin via non-F(ab')2 binding sites, and to determine the effect of phase changes of phospholipid on reactivity of aCL. Variables measured will include temperature, ionic strength, and micelle vs liposome presentation of phospholipid. Secondly, affinity-purified aCL and/or (from other sources) monoclonal aCL will be examined for activity in cell biology systems. These will include: direct test for anti-coagulant activity (especially in antibody derived from patients without lupus anticoagulant), inhibition of phosphatidyl inositot-dependent endocrine and lymphocyte function, activity in platelet aggregation assays, and reactivity against placental tissue. Later experiments will test infusions of antibody into pregnant small animals for both in vivo localization of antibody and ability to disrupt pregnancy. Thirdly, the relationship between aCL and infectious disease will be clarified by testing affinity-purified aCL for reactivity with infectious organisms and by monitoring serum aCL activity in spontaneously infected patients. In addition there will be ample opportunity to examine clinical correlations of aCL with clinical syndromes. The proposed experiments promise to provide explanations at a basic level for the pathophysiology of what is currently known only as an association between clinical events and serologic abnormalities. The sought explanations have importance not only for SLE but for infertility and for basic biology as well.